Azodicarbonamide inhibits HIV-1 replication by targeting the nucleocapsid protein

Nucleocapsid p7 (NCp7) proteins of human immunodeficiency virus type 1 (HIV-1) contain two zinc binding domains of the sequence Cys-(X)(2)-Cys-(X)(4)-His-(X)(4)-Cys (CCHC)(1,2). The spacing pattern and metal-chelating residues (3 Cys, 1 His) of these nucleocapsid CCHC zinc fingers are highly conserved among retroviruses(1,3,4). These CCHC domains are required during both the early(5,6) and late(7,8) phases of retroviral replication, making them attractive targets for antiviral agents. Toward that end, we have identified a number of antiviral chemotypes that electrophilically attack the sulfur atoms of the zinc-coordinating cysteine residues of the domains(9-14). Such nucleocapsid inhibitors were directly virucidal by preventing the initiation of reverse transcription(15) and blocked formation of infectious virus from cells through modification of CCHC domains within Gag precursors(16). Herein we report that azodicarbonamide (ADA) represents a new compound that inhibits HIV-1 and a broad range of retroviruses by targeting the the nucleocapsid CCHC domains. Vandevelde et al.(17) also recently disclosed that ADA inhibits HIV-1 infection via an unidentified mechanism and that ADA was introduced into Phase I/II clinical trials in Europe for advanced AIDS. These studies distinguish ADA as the first known nucleocapsid inhibitor to progress to human trials and provide a lead compound for drug optimization.